SHP2 mutations induce precocious gliogenesis of Noonan syndrome-derived iPSCs during neural development in vitro

Abstract

Abstract Background Noonan syndrome (NS) is a developmental disorder caused by mutations of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2). Although NS patients have diverse neurological manifestations, the mechanisms underlying the involvement of SHP2 mutations in neurological dysfunction remain elusive. Methods Induced pluripotent stem cells generated from dermal fibroblasts of three NS-patients (NS-iPSCs) differentiated to the neural cells by using two different culture systems, 2D- and 3D-cultured systems in vitro. Results Here we represent that SHP2 mutations cause aberrant neural development. The NS-iPSCs exhibited impaired development of EBs in which BMP and TGF-β signalings were activated. Defective early neuroectodermal development of NS-iPSCs recovered by inhibition of both signalings and further differentiated into NPCs. Intriguingly, neural cells developed from NS-NPCs exhibited abundancy of the glial cells, neurites of neuronal cells, and low electrophysiological property. Those aberrant phenotypes were also detected in NS-cerebral organoids. SHP2 inhibition in the NS-NPCs and NS-cerebral organoids ameliorated those anomalies such as biased glial differentiation and low neural activity. Conclusion Our findings demonstrate that SHP2 mutations contribute to precocious gliogenesis in NS-iPSCs during neural development in vitro.

Keywords

• Noonan syndrome
• Induced pluripotent stem cells
• SHP2 mutations
• Neural development
• Gliogenesis
• Cerebral organoids